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Raf Signaling but not the ERK Effector SAP-1 Is Required for Regulatory T Cell Development¹

Jane E. Willoughby^*, Patrick S. Costello^*, Robert H. Nicolas^*, Nicholas J. Robinson, Gordon Stamp, Fiona Powrie and Richard Treisman^2,*

^* Transcription Laboratory, Experimental Pathology Laboratory, Cancer Research United Kingdom London Research Institute, Lincoln’s Inn Fields Laboratories, London, United Kingdom; and Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Regulatory T cells (T_reg) play an important role in immune regulation. Their development in the thymus requires TCR activation and recognition of peptide-MHC, although the downstream signals controlling commitment to the lineage are unclear. To compare the requirements for positive selection and T_reg development, we studied knockout and transgenic mice defective in Raf signaling and the ERK effector SRF accessory protein 1 (SAP-1), a member of the ternary complex factor family of Ets domain transcription factors. Although SAP-1 deficient mice display a severe defect in thymocyte positive selection, T_reg development was unimpaired as assessed by expression of Foxp3 and the activation markers CD25, GITR, CTLA4, and CD103 in the CD4⁺ cell population. In contrast, inhibition of Raf signaling by the interfering dominant negative Raf derivative reduced both Foxp3⁺ and Foxp3^– CD4⁺ populations. In SAP-1-deficient CD4⁺CD25⁺ T_reg cells, TCR crosslinking efficiently induced ERK activation, but transcriptional induction of the immediate early gene Egr-1 was impaired. Nevertheless, neither deletion of SAP-1 nor expression of a dominant negative Raf derivative affected the ability of CD4⁺CD25⁺ T_reg cells to suppress CD4⁺CD25^– cell proliferation in vitro. Finally the suppressive activity of CD4⁺CD25⁺ T_reg cells lacking SAP-1 in an in vivo colitis model was not significantly impaired. The signaling requirements for development of T_reg cells in the thymus are thus distinct from those required for "conventional" T cell positive selection, and ERK signaling to SAP-1 is not required for the suppressive activity of T_reg cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by Cancer Research U.K. J.W. was additionally supported by a grant from the Medical Research Council. F.P. and N.R. are supported by the Wellcome Trust.

² Address correspondence and reprint requests to Dr. Richard Treisman, Cancer Research United Kingdom London Research Institute, Lincoln’s Inn Fields Laboratories, 44 Lincoln’s Inn Fields, London, United Kingdom. E-mail address: richard.treisman{at}cancer.org.uk

³ Abbreviations used in this paper: SRF, serum response factor; SAP-1, SRF accessory protein 1; TCF, ternary complex factor; T_reg, regulatory T cells; DP, double positive; PBDu, phorbol dibutyrate; WT, wild type; SP, single positive; DN, dominant negative; p-ERK, phospho-ERK.

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